Opioid (narcotic) analgesics and antagonists. Non-opioid (non-narcotic) analgesics

1. ZAPORIZHZHIA STATE MEDICAL UNIVERSITY PHARMACOLOGY DEPARTMENT

LECTURE № 4
OPIOID (NARCOTIC) ANALGESICS and ANTAGONISTS.
NON-OPIOID (NON-NARCOTIC) ANALGESICS.
Lecturer – Assoc. Prof. Irina Borisovna Samura
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OPIOID AGONISTS and ANTAGONISTS
1. FULL AGONISTS:
Morphine hydrochloride Tab. 0.01 g; amp. 1% -1 ml
Omnopon – amp. 1% solution - 1 ml
Promedole (Trimeperidine)-amp. 1% - 1 ml, Tab. 0.025 g
Fentanyl – amp. 0.005% - 1 ml
2. PARTIAL AGONISTS, or Agonists-Antagonists:
Pentazocine – amp. 3%-1 ml, Tab. 0.05 g
Tramadol – caps. 0.05; amp. 5%-1 ml
Nalorphine – amp. 0.5%-1 ml and 0.05%-0.5 ml
Buprenorphine – Tab. 0.0002
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3. Antagonists:
Naloxone – amp. 0.04% - 1 ml
Naltrexone – Tab. 0.01 ; 0.05 g
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OPIATES (Opium Alkaloids)
1. Phenantrenes:
Morphine
Codeine
Omnopon
Aethylmorphine
2. Isoquinolines:
Papaverine hydrochloride
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OPIATE RECEPTORS
μ-Rs: Supraspinal Analgesia,
Euphoria / Sedation,
Respiratory Depression,
GIT Motility,
Smooth Muscle Spasm, Miosis
κ-Rs: Spinal Analgesia,
Sedation / Dysphoria, Miosis
σ-Rs: Dysphoria, Psychotomimetic effects,
Respiratory and Vasomotor Stimulation,
Mydriasis
δ-Rs: Euphoria, Convulsive activity
ε-Rs: β-endorphine-like Analgesia
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MECHANISM OF ACTION:
Stimulation of Opioid Receptors through Gi-Proteins =>
inhibition of Adenylyl Cyclase
K+ Efflux (Hyperpolarization)
Ca2+ Influx
=> impeding Neuronal Firing and
Transmitter Release
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PHARMACOLOGICAL EFFECTS
CNS: Euphoria, Drowsiness, Apathy,
Mental Confusion, Nausea and Vomiting
Respiratory:
Tidal Volume
Respiratory Rate
Antitussive effects: a direct suppression of
the Cough Reflex Center
Cardiovascular: Peripheral Vasodilation
Total Peripheral Resistance
Histamine Release =>
Flushing, Red Eyes, Sweating
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GIT:
Inhibition of peristalsis => Constipation
Sphincter of Oddi spasm, nausea
Gastric, Biliary, and Pancreatic Secretions
Tone in the Biliary Tract => Biliary Spasm
Amylase and Lipase levels up to 15 times
Urinary tract:
Smooth Muscle tone and spasms
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11. Clinicall uses of MORPHINE

ANALGESIA:
Renal or Biliary Colic
Myocardial Infarction
Acute Trauma
Postoperative Pain
Terminal Cancer
PULMONARY EDEMA
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12. OVERDOSE with MORFINE

Respiratory and CNS Depression, Miosis
BP
HR
t°
Skin is bluish and cold, face is pale,
Urine Retention, bladder overflowed,
Circulatory Collapse,
Pulmonary Edema, Convulsions,
Shock, Apnea, Cardiopulmonary Arrest
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13. Treatment of overdose with Morphine

Narcotic antagonist: NALOXONE 0.4 mg/ml
IV bolus 0.8-2 mg (2-5 ml) q2-3 min to a total dose 10 mg
Symptomatic treatment:
Cordiamine, Sulfocamphocaine,
Atropine, Coffeine
Continued Respiratory Support
Correction of Fluid and Electrolyte Imbalance
FORCED DIURESIS:
5% Glucose 500-800 ml
0.9% NaCl isotonic solution
4% NaHCO3
FUROCEMIDE 0.1% 4-8 ml
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Promedole amp. 1% -1 ml, Tab. 0.025 g,
a synthetic opioid, Piperidine Compound
Binds to opioid Rs, particularly κ-Rs
It is preferred for analgesia during LABOR –
Neonatal Respiratory Depression is less marked
and it does not interfere with Uterine Contractility
It is often used in minor procedures like dilatation
and curettage.
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Fentanyl amp. 0.005%-1 ml
is chemically related to Promedole,
has 80 times the analgesic potency of
Morphine.
has a rapid onset and short duration of action
(15-30 min)
FENTANYL + DROPERIDOL
produce a NEUROLEPTANALGESIA
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Pentazocine amp. 3%-1 ml,Tab. 0.05
agonist - κ-Rs and σ-Rs
antagonist - μ and δ-Rs
Activates Rs in the spinal cord, and is used
to relieve moderate pain
In angina:
Aortic pressure
Pulmonary AP => Heart Work
Renal plasma flow
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TRAMADOL caps. 0.05 g; amp. 5%-1 ml
a centrally acting weak synthetic opioid
with μ agonist effect and inhibitory action on
Noradrenaline and Serotonin reuptake in the CNS.
T1/2 = 6 hours
is only partially antagonized by Naloxone.
Adverse reactions: Dizziness, Headache, somnolence, CNS
stimulation, euphoria, anxiety, coordination disturbance,
seizures, vasodilation, anorexia, dry mouth,
urine retention, respiratory depression.
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Naloxone amp. 0.04%-1 ml - a pure Antagonist.
antagonizes most of the opioid effects:
respiratory depression, sedation, and hypotension
Duration of action 1-4 hours
Clinical uses:
Treatment of acute opioid overdose
Postoperative narcotic depression
Diagnosing opiate dependence
Septic shock
Adversed effects: HR, AP, ventricular fibrillation,
cardiac arrest; tremors and withdrawal symptoms in
narcotic-dependent patients, diaphoresis, seizures,
pulmonary edema.
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Naltrexone - Tab. 0.05 g (50 mg)
T1/2 = 10 hours.
A single oral dose of 100 mg (2 tab.) blocks virtually
all effects of a dose of heroin for up to 48 hours.
PO 30-50 mg => minimal analgesia, only slight
drowsiness, and no respiratory depression.
Psychotomimetic effects, AP
Clinical uses:
Adjunct for maintenance of opioid-free state in
detoxified individuals;
Alcoholism.
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20. Drugs from other groups with analgesic activity

α2 – Adrenomimetics: Clopheline
Tricyclic antidepressants: Amitriptyline
Imizine
Antiepileptic drugs: Carbamazepine
Sodium Valproate
GABA-receptors’ agonists: Baclophene
Hormones: Somatostatin, Calcitonin
Drugs for narcosis: Nitrous oxide (N2O)
Ketamine
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21. NON-OPIOID ANALGESICS

1.Para-Aminophenol Compounds
Paracetamol (Acetaminophen, Panadol)
Phenacetin
2. Salicylates – Salicylic Acid Compounds
Acetylsalicylic Acid (Aspirin)
Sodium Salicylate
3. Pyrazolone Compounds
Analgin (Metamizole)
Butadione (Phenylbutazone)
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4. Antranil Acid Compounds
Mephenamic Acid
5. Indole-Acetic Acid Compounds
Indometacin
6. Phenyl-Acetic Acid Compounds
Diclofenac-Sodium
7. Phenyl-Propionic Acid Compounds
Ibuprophen
8. Naphtyl-Propionic Acid Compounds
Naproxen
- oxicams :
Piroxicam
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COX-2 inhibitors:
Meloxicam
Celecoxib
Nimesulide
COX-1 is structural and responsible for PROTECTIVE
PROPERTIES of GIT.
COX-2 is induced and responsible for
PG production by cells involved in
INFLAMMATION.
COX-3 is located in the CNS
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Para-Aminophenol Compounds:
● Paracetamol
● Phenacetin
Mechanism of action: inhibition of COX-3
1) Antipyretic action:
Inhibition of COX-3 => PG synthesis in the CNS
2) Analgesic action:
is related to an elevation of the pain threshold.
Tab. «Citramon»:
Aspirin 0.2 g
Phenacetin 0.2 g
Caffeine 0.04 g
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ADVERSE EFFECTS
Hemologic: hemolytic anemia, neutropenia,
leukopenia, thrombocytopenia
Hepatic: Liver Damage (toxic doses),
Rash, Hypoglycemia
Hepatic enzymes
dizziness, excitement, disorientation.
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Large doses of Paracetamol ( 7-10 g) =>
Hepatocellular damage with central lobular necrosis
Renal tubular necrosis
The liver toxicity: due to toxic metabolite
N-acetyl-P-benzoquinonamine, which normally turns
harmless by Conjugation with Glutathione.
TREATMENT:
Sulfhydryl SH- compounds:
Acetylcysteine (ACC)
Cystamine
Methionine
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Aspirin is a weak organic acid that is unique among
the NSAIDs in irreversibly acetylating (inactivating)
COX-1 and COX-2.
NSAIDs have 3 major therapeutic actions:
Antinflammatory
Analgesic
Antipyretic
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29. MECHANISM OF ASPIRIN ASTHMA DEVELOPMENT

ARACHIDONIC ACID
COX
LO
PGE COX
Inhibitors
PGE
PGF PGF
PGE
PGF
PGE
PGE
PGE
PGF
PGF
LTC,D,E
LTC,D,E
PGF PGF
PGE
LTC,D,E
LTC,D,E
PGF
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LTC,D,E
LTC,D,E
LTC,D,E

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THERAPEUTIC USES of SALICYLATES
1. Antipyretics and analgesics:
Gout, Rheumatic Fever, Rheumatoid Arthritis.
headache, arthralgia, and myalgia.
2. External applications:
Salicylic acid is used topically to treat calluses and
epidermophytosis
Methyl salicylate –
externally as a cutaneous counterirritant
3. Cardiovascular applications:
Aspirin 170-350 mg
4. Colon cancer
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ADVERSE EFFECTS of SALICYLATES
1. GIT: nausea, vomiting, bleeding, ulceration
2. Blood: Prothrombin
Aspirin should not be taken for at least 1 week prior to
surgery.
3. Respiration: Respiratory Alkalosis and
true Metabolic Acidosis.
4. Metabolic processes: hyperthermia
5. Hypersensitivity: Urticaria, Bronchospasm,
Lyell's syndrome (Epidermal Necrolysis),
Angioneurotic Edema, Anaphylactic Shock
6. Reye's syndrome:
HEPATITIS with CEREBRAL EDEMA
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SALICYLISM - a condition of mild salicylate intoxication:
nausea, vomiting, hyperventilation,
headache, mental confusion,
dizziness, tinnitus (ringing in the ears),
tachypnoea and respiratory alkalosis
SEVERE SALICYLATE INTOXICATION :
restlessness, delirium, hallucinations,
convulsions, coma,
Respiratory Alkalosis + Metabolic Acidosis,
Death from respiratory failure.
Treatment: gastric lavage, correction of hyperthermia,
IV fluids
Dialysis (hemodialysis or peritoneal dialysis)
Correction of acid-base and electrolyte balances:
Urinary Alkalinization: normal 0.9% NaCl saline solution
containing 2% glucose solution and
2% Sodium Bicarbonate solution at the rate of 2 liters/hour.
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Analgin (Metamizole) Tab. 0.5 g, amp. 25%-2 ml
Antipyretic action - by direct action
on the hypothalamic heat-regulating center to block
the effects of Endogenous Pyrogens IL1,TNF-α
=> heat dissipation through sweating and
vasodilation
T1/2 = 72 hours.
Clinical uses: moderate to severe pain including
headache, toothache, neuralgia, and myalgia
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Analgin is a major cause of
AGRANULOCYTOSIS
Phenylbutazone (Butadion)
Diclofenac-natrium
Indometacin
can cause APLASTIC ANEMIA.
=> Should be used ONLY when ASPIRIN and
other safer NSAIDs are ineffective.
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Indomethacin is more effective in relieving inflammation
with acute gouty arthritis, osteoarthritis of the hip,
ankylosing spondylitis, and uveitis,
postoperative ophthalmic procedures,
Indomethacin can delay labor by suppressing
uterine contractions.
Indomethacin has been recommended as
a Tocolytic in Preterm Labour < 32 weeks of
gestation.
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Diclofenac-Natrium (VOLTAREN)
Tab. 0.025 g; amp. 2.5%-3 ml
a Potent COX inhibitor with Antiinflammatory,
Analgesic, and Antipyretic properties
more potent than Indomethacin
Adverse effects: 20% of patients GIT distress,
Occult GIT Bleeding,
Gastric Ulceration,
Hepatic Enzyme Levels
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Ketorolac
Tab. 10 mg (0.01 g),
amp. 3%-1 ml IM,
ophthalmic drops: 0.5% solution
Effective Analgesic in patients with
moderate to severe postoperative pain.
as effective as Morphine, and have fewer side effects, in
surgical and chronic cancer pain.
has longer duration of action (T1/2 = 5 hours) and acts like
the other NSAIDs
has less antinflammatory activity
Clinical uses: postoperative pain, cancer pain,
topically for allergic conjunctivitis
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Selective COX-2 inhibitors
Meloxicam Tab. 0.015 g
Celecoxib Caps. 0.1 g
Advantage: fewer Gastric Ulcers and do not inhibit
platelet aggregation
Disadvantage: may have prothrombotic effect, leading to a
higher incidence of Cardiovascular Events.
Adverse reactions:
Renal Toxicity – Renal blood flow, Edema, Hypertension
Interfere with Wound (Ulcer) Healing, Bone Remodeling,
Prenatal Renal Development
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39. Mechanism of Cardiovascular Disorders Development

ARACHIDONIC ACID
COX-1
COX-2
TXА2
Prostacyclin (PgI2)
COX-2
inhibitors
Thrombus
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Rofecoxib, Valdecoxib, Nimesulide –
have been withdrawn from the pharmaceutical market:
Rofecoxib and Valdecoxib have been reported to be
associated with increased incidence of
MYOCARDIAL INFARCTION and STROKE,
Nimesulid - due to its high HEPATOTOXICITY.
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THANK YOU for ATTENYION!
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